11alpha-lower alkyl steroids



Ila-LOWER ALKYL STEROIDS Gunther S. Fonken and John A. Hogg, KalamazooTownship, Kalamazoo County, and Barney J. Magerlein, Kalamazoo, Mich.,assignors to The Upjohn Company, Kalamazoo, Mich., a corporation ofMichigan No Drawing. Application September 27, 1956 Serial N0. 612,365

2 Claims. (Cl. 260-3975) This invention relates to1la-lower-alkyl-hydrocortisone and 2l-esters thereof, intermediates inthe production thereof, and to a process for their production.

It is an object of the present invention to provide 11-lower-alkyl-hydrocortisone, especially lla-methyl-hydrocortisone and21-esters thereof. Another object is the provision of novelintermediates in the production thereof. A further object is theprovision of a process for the production thereof. Other objects will beapparent to those skilled in the art to which this invention pertains.

This-application is a continuation-in-part of application Serial Number510,516, filed May 23, 1955.

The 11a-lower-alkyl-hydrocortisone and 21-esters thereof, especiallyllu-methyl-hydrocortisone and its 21-acetate, have anti-inflammatoryactivity and are useful in the treatment of rheumatoid arthritis andother inflammatory conditions of the skin, eyes and ears of humans andvaluable domestic animals which are due to a variety of bacterial andfungal infections, contact dermatitis and other allergenic reactions.

The novel 1la-lower-alkyl-hydrocortisones and intermediates in theproduction thereof may be represented by the following formulae:

CH CH3 (llHr-O-Ac CHr-O-Ao CH CH 2,880,215 Patented Mar. 31, 1959 CH CH5?H2-O-R' (fHr-OH CH CH lower-alkyl lower-alkyl HO HO CH CH3 R 0: v V VICH3 C 8 CHr-O-R" (|'2H2-O-A0 (3:0 CH lower-alkyl loweralkyl Ho HO CH1CH3 VIII VII wherein Ac is the acyl radical ofa hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive, R is aketone protecting group, i.e., a cyclic ketal or an enol ether, R is ahydrocarbon radical containing from one to twenty carbon atoms, and R"is hydrogen or Ac as defined above. In Formulae II, III, IV and V, whenR is an enol ether group, an additional double bond in the 3(4) positionis present in the molecule. The term lower-alkyl, when used herein,means alkyl containing from one to eight carbon atoms, inclusive.

The starting 21-acyloxy 4,17(20) preguadiene-3,1l dione (I) can beprepared as disclosed in the copending application of Hogg, Beal andLincoln, U. S. Patent 2,735,856, i.e. treatment of ll-ketoprogesteronewith about a molar equivalent of sodium 'methoxide and an excess ofdiethyl oxalate in dry benzene and then brominating the thus-producedsodium enolate of 11 keto-21-ethoxyoxalylprogesterone with two molarequivalents of bromine in methanol containing potassium acetate.Reacting the dibrominated product with more than two molar equivalentsof sodium methoxide in the same solvent is productive of methyl3,11-diketo-4,l7(20) [cis]pregnadiene-21-oate. Refluxing this compoundin methanol containing sodium methoxide converts it to the trans isomer.Ketalizing the S-keto group of either the cis or trans isomer of methyl3,l1-diketo-4,l7(20)- pregnadiene-Zl-oate with ethylene glycol in theusual manner, followed by the reduction of the ketalized compound withlithium aluminum hydride in ether and then hydrolysis of the ketalizedreduced compound with dilute hydrochloric acid in acetone at roomtemperature, is productive of the corresponding cis or trans isomer ofl1B,21-dihydroxy-4,l7(20) pregnadiene-3-one. Esterir fication of the21-hydroxy group-of these compounds with, the usual acylatingderivatives of a hydrocarbon -carboxylic acid containing from one totwelve carbon atoms,

inclusive, preferably acetic acid, is productive of the correspondingcis or trans isomer of llfl-hydroxy-Zl:acyloxy-4,l7(20)-pregnadiene-3-one. Oxidation of the ll-hydroxy group ofthese compounds with N-bromoacetamide in pyridine for eighteen hours orchromic acid .ilI fiCCfiC'flCid andwaterisproductive of thecorresponding cis or trans isomerof"21-acyloxy-4,17(20)-pregnadiene-3,11-dione (I).

In the reactions described hereinbelow, the preferred compounds I-VIIIhave the 17(20)-cis configuration. The cis isomers of VII can beconverted in higher yield to VIII than the corresponding trans isomers.

In carrying out the ketone protecting step, a 21-acyloxy-4,17(-pregnadiene-3,1l-dione (I), preferably21-acetoxy-4,17.(20)-[cis]-pregnadiene-3,11=dione, is ketalized with an.a-glycol or S-glycol containing from one to eight carbon atoms,inclusive, e,g., ethylene glycol, .propylene glycol, vtrimethyleneglycol, octane-1,2-diol, to produce the 3-ketal thereof (II) wherein Ris an alkylene dioxy group, orreacted with methyl alcohoL. ethylalcohol, benzyl alcohol, octyl-alcohol, under the usual'enoletherification conditions, to produce a 3,-enol ether thereof v(II)wherein R is a hydrocarbonoxy radical containing from one to twentycarbon'atoms, inclusive, and adouble bond is present in the3,(4)-position.

The removal of the 21-ester group of the 3-ketone-protected21racyloxy-5,17(20)-pregnadiene-3,1l-dione (II) preferably the3-ethylene glycol ketal of 21-acetoxy-4,17(20)-[cis]-pregnadiene-3,1l-dione, involves a hydrolysis under theusual, alkaline conditions. Although strong alkali, e.g., sodiumhydroxide, can be employed, we have found that satisfactory results areobtained when employing an alkaliemetal bicarbonate, preferably in anoxygen-free atmosphere. Hydrolysis of the 2l-acyloxy group produces thecorresponding 3-ketone protected 21-hydroxy-5,17(20)-pregnadiene-3,'1l-dione (III).

The 21-.etherification step involves the conversion of the 21-hydroxygroup of a 3-ketone-protected 2l-hydroxy- "5,17(20)-pregnadiene3,ll-dione (III),-preferably 3-ethylene glycol ketalof21-hydroxy-4,17(20)-[cis]-pregnadiene-3,ll-dione, to a'21-hydrocarbonoxy group, i;e., etherification of the 2.1-hydroxy groupto produce the corresponding 3-ketone protected '21-hydrocarbonoxy-5,17(20)-pregnadiene-3,1l-dione (IV). This can be accomplished by theusual etherification procedure, e.g., by reaction of a hydrocarbonhalide or alcohol with III. The reaction is usually performed in thepresence of an aromaticheterocyclic amine when a hydrocarbon halide isemployed or in the presence of boron trifiuoride or 'p-toluenesulfonicacid when an alcohol is employed. An

:enol ether can also be prepared by reaction of the 21- hydroxy groupwith a readily enolizable ketone, e.g., dihydropyran, as disclosed inUS. Patent 2,637,728.

Examples of 2'1-ethers which can be produced 'are the lower-alkylethers,=e.g., methyl,ethyl, propyl, butyl, amyl, hexy'l, heptyl,octyl,and aralkyl, e.g., benzyl, triphenylmethyl, etc.

.An alternative route'to a3-ketalized 21-etherified 21-'hydroxy-5,17(20)-pregnadiene-3,ll-dione (IV) involves the reaction of a3-ketal of l1,8,2l-dihydroxy-4,l7(20)- 'pregnadiene-3-one with anetherifying agent as described above to produce a 3-ketal ofI1fi-hydroxy-21-hydrocarbonoxy-4,17(20)-pregnadiene-3-one and thenoxidizing the llfi-hydroxy group with chromic acid in acetic acid orN-bromoacetamide in pyridine, in the usual manner.

The alkylation step involves the reaction of a 3-ketoneprotected21-hydrocarbonoxy-5,17(20)-pregnadiene-3,1 1- dione(IV), preferably the3-ethylene glycol ketal of 21- triphenylmethoxy 4,17(20) [cis]pregnadiene-3,11-dione, with a lower-alkyl lithium, e.g., methyl, ethyl,propyl, butyl, amyl, hexyl, heptyl -or octyl lithium, preferably methyllithium, to-produce the corresponding 3- ketone-protected 1 1u-lower-alkyll1 3-hydroxy-2 l-hydrocarbonoxy-5,17(20)rpregnadiene-3-one(V). The loweralkyl magnesium halides ordinarily are not reactivetoward'the ll-keto group whereas the lower-alkyl lithiums, andespecially methyl lithium, react rapidly and with ease with the ll-ketogroup. The usual reaction conditions for an alkylation with alower-alkyl lithium are employed. Usuallya reaction'temperature ofabout-room tempere "du'cing '5,17-(20)-pregnadiene-3-one as theintermediate com- 'ket'onep'rote'cted steroid (V) is mixed with. ahydroly'zing agent such as,. for example, .dilute aqueous hydrochloricacid, sulfuric acid, or other acetic hydrolyzing a'g'ent. Although bothof these groups are ordinarily removed in the samereaetion,:theirremova1 can b'e"stepwi'se, with theB-ketOne-protecti'n'ggroupbeingremoved first, if so desired. The3'-'ketone protecting group is ordinarily more susceptible to hydrolysisthan the 21-ether group and is therefore more rapidly hydrolyzed toproduce an llu-lower-alkyl 11B hydroxy- 21 hydrocarbonoxy4,l7(20)-pregnadiene 3 one. A 21 tetrahydropyranyl ether, however, ishydrolyzed as rapidly or moreso than the corresponding'3-ketone-protectin'g group, thus-pro- 3-ketalized 1 la'lower-al-kyl-l1B, 21-dihydroxypound in the hydrolysis reaction. A

Est'e'rific'ati'on of an 1la-lower-alkyl-l1Z3,21-dihydroxy-4,17(20)-pregnadiene3-one (VI), preferably ll'az r'neth'yl- 115,21-dihydroxy-4, 17 (20) [cis] -p'regnadiene-3-one with an esterifyingderivative of a hydrocarbon carboxylicacid containing from one to twelvecarbon atoms is productive of the corresponding '1la-lower-alk'yl-llfi-hydroxy 2lacyloxy-4,17 20)-pregnadiene-3-one (VII).This reaction can be performed under the est'er'ifications known in theart, 'e.g., by the reaction of VI with the selected-acid anhydride oracid chloride or bromide of a hydrocarbon carboxylic acid, preferably inthe presence of pyridine or like tertiary aromatic amine, or by reactionwith the selected acid, in the presence of an esterific'ation catalystor with an ester under ester exchange conditions. Reaction conditionswhich are apt to affect the labile 11f hydroxy group should be avoided.Compounds thusproduced include the compounds represented by Formula VIIwherein the 17(20) configuration is cis, the ll-loweralkyl group ismethyl and Ac is the acyl radical of a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive, e.g., formic,propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic,Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic,triethylacetic, heptanoic, octanoic, a-ethylisovaleric, a cyclic acid,e.g., cyclopropylideneacetic, cyclop'e'ntylformic, cyclopentylacetic,fi-cyclohexylpropionic, fi=cyclopentylpropionic, cyclohexylformic,cyclohe'xylacetic, an aryl or alkaryl acid, e.g., benzoic, 2-, 3-, or4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic,ethylbenzoic, 2,4,6-trimethylbenzoic 2,4,6-triethylbenzoic, a-naphthoic,3-methyl-ix-naphthoic, an aralkyl, e.g., phenylacetic, phenylpropionic,diphenylacetic, triphenylacetic, etc.

The oxidative hydroxylation reaction of the present invention converts a1la-lower-alkyl-llfl-hydroxy-Zlacyloxy-4,17(20)-pregnadiene-3-one (VII),preferably Ila-methyl 11,9 hydroxy 21acetoxy-4,l7(20)-[cislpregnadiene-S-one, to the correspondinglla-lower-alkyl- 11/3,17m-dihydroxy 21 acyloxy 4,- pregnene'3,20-dione(VIII) by reaction with a catalytic amount of osmium tetroxide and anoxygen donating oxidizing agent. Included among the oxidizing agents arehydrogen peroxide, peracids, alkyl peroxides, amine oxide peroxides,etc. The preparation of a number of these oxidiiing agents and thereaction conditions which are preferably employed are discussed morefully in the copending application of Lincoln and Hogg, 476,061, filedDecember 17, 1954.

A preferred procedure involves employing from about two to about threemolar equivalents of the oxidizing agent and less than 0.05 molarequivalent of osmium tetroxide, calculated on the starting steroid, intertiary butyl alcohol at about room temperature.

Substituting an 11u-lower-alkyl 1119,21 dihydroxy-4,17(20)-pregnadiene-3-one for the corresponding 21- acyloxy compound asthe starting steroid in the oxidative hydroxylation step is productiveof the corresponding 1 la-lower-alkyl-l 1fi,17a,21-trihydroxy 4pregnene-3,20- dione.

The following preparations and examples are illustrative of the productsand process of the present invention, but are not to be construed aslimiting.

PREPARATION 1 The 3-ethylene glycol ketal of 21 -acetoxy-4,17(20)-[01's]- pregnadiene-3,1 1 -dine (II) A solution of 0.50 gram (1.35millimoles) of 21- acetoxy-4,17(20)-[cis]-pregnadiene-3,11 dione,prepared as disclosed in the copending application of Hogg et al., US.Patent 2,735,856, ten milligrams of para-toluenesulfonic acid and twomilliliters of ethylene glycol in 100 milliliters of benzene wasrefluxed for six hours with concomitant removal of the water of reactionby passing the return condensate through a bed of calcium carbide. Thecooled solution was then washed with an aqueous four percent solution ofsodium bicarbonate, water and then dried. The dried solution wasdistilled at reduced pressure leaving a yellow oil which sooncrystallized. The crystals were recrystallized from a mixture of ethylacetate and Skellysolve B (hexane hydrocarbons) to give 0.27 gram of the3-ethylene glycol ketal of 2l-acetoxy-4,l7(20)-[cis]-pregnadiene-3,1l-dione melting at 160 to 162 degreescentigrade and having the analysis below.

Calculated for C H O C, 72.43; H, 8.27. Found: C, 72.11; H, 8.44.

PREPARATION 2 The 3-ethylene glycol ketal of 21 -hydr0xy-4,1 7 (20)-[cis]- pregnadiene-3,11-di0ne (III To a solution of ten grams (0.024mole) of the 3-ethylene glycol ketal of21-acetoxy-4,l7(20)-[cis]-pregnadiene- 3,11-dione in 1,500 millilitersof absolute methanol, in a nitrogen atmosphere, was added a solution often grams (0.1 mole) of potassium bicarbonate in 100 milliliters ofwater at a temperature of about 25 degrees centigrade. The mixture wasstirred for one hour and then maintained at room temperature foreighteen hours, in a nitrogen atmosphere. The mixture was distilled to asmall volume at reduced pressure and then diluted with stirring with 500milliliters of water. Crystals precipitated from the mixture which werefiltered, washed with water, and dried to give 8.46 grams of the3-ethylene glycol ketal of 21-hydroxy-4,l7(20)-[cis]-pregnadiene-3,ll-dione melting at 109 to 111.5 degrees centigrade. Recrystallization ofthis product from fifty percent aqueous methanol gave crystals meltingat 113.5 to 115 degrees centigrade and having the analysis below:

Calculated for C l-1 0 C, 74.16; H, 8.66. Found: C, 74.05; H, 8.95.

PREPARATION 3 The S-ethylene glycol ketal of 21 -triphenylmelhoxy- 4 ,17 (20) -[cis]-pregnadiene-3,l I-dione (IV) A solution of 5.38 grams(0.144 mole) of the 3-ethylene glycol ketal of2l-hydroxy-4,l7(20)-[cis]-pregnadiene-3,l1-dione and 4.4 grams oftriphenylmethyl chloride in seventy milliliters of dry pyridine wasmaintained at about 25 degrees centigrade for 52 hours. The solution wasthen poured into a mixture of ice and water and then extracted with a1:1 mixture of ether and benzene followed by extractions with three-milliliter portions of ether. The combined extracts were washed severaltimes with water and then dried with anhydrous potassium carbonate. Thedried solution was distilled to dryness leaving a glass which wascrystallized from methanol to give 6.19 grams of the 3-ethylene glycolketal of 21-triphenylmethoxy-4,17(20)-[cis]-pregnadiene- 3,11-dionemelting at to 198 degrees centigrade. Recrystallization from a mixtureof ether and methanol raised the melting point to 201 to 203 degreescentigrade. These crystals had the analysis below.

Calculated for C H O C, 82.05; H, 7.54. Found: C, 81.99; H, 7.47.

PREPARATION 4 The 3-ethyl enol ether of 21-acetoxy-4,17(20)-[cis]-pregnadiene-3,1 1 -di0ne A solution of 0.50 gram (1.35 millimoles) of21-acetoxy-4,17(20)-[cis]-pregnadiene-3,l l-dione is reacted withp-toluenesulfonic acid and ethanol following the procedure ofPreparation 1, except that ethanol, as noted previously, is substitutedfor the ethylene glycol used in Preparation 1. The product, the 3-ethylenol ether of 21-acetoxy-4,l7(20)-[cis]-pregnadiene 3,11 dione, is awhite crystalline solid.

EXAMPLE 1 The 3-ethylene glycol ketal of 11ot-methyl-11fl-hydroxy- 21triphenylmethoxy 4,17 (20)-[cis]-pregnadiene-3- one (V) To a solution of300 milligrams of the 3-ethylene glycol ketal of21-triphenylmethoxy-4,l7(20)-[cis]-preg:

nadiene-3,11-dione in five milliliters of anhydrous benzene in a dryatmosphere of nitrogen was added ten milliliters of a 0.33 molarsolution of methyl lithium in anhydrous ether. The sealed containercontaining the solution was maintained for three days at about 25degrees centigrade.

The solution was diluted with benzene and then washed with sixmilliliters of a 1:5 solution of acetic acid in water and then withseveral portions of water. The benzene solution was dried and thendistilled to dryness.

The residue was chromatographed over a thirty gram colum of Florisil(synthetic magnesium silicate). The

column was developed with sixty-milliliter portions of Skellysolve B(hexane hydrocarbons) containing increasing proportions of acetone. A294 milligram yield of the 3-ethylene glycol ketal oflla-methyl-llp-hydroxy- 21 triphenylmethoxy-4,17(20)-[cis]-pregnadiene-3-one was eluted from the column withSkellysolve B plus five percent acetone. The thus purified material wasrecrystallized from a mixture of ethyl acetate and methanol to giveproduct melting at 182 to 184 degrees centigrade and having the analysisbelow.

Calculated for C H O C, 81.87; H, 7.93. Found:

EXAMPLE 1A The 3-ethyl enol ether of IIa-methyI-IIfi-hydrOxy-ZI-triphenyImethoxy-4,17(20) -[cis]-pregnadiene-3-0ne The product ofPreparation 4, the 3-ethy1 enol ether of2l-acetoxy-4,17(20)-[cis]-pregnadiene-3,1l-dione, was hydrolyzed withpotassium bicarbonate following the procedure of Preparation 2 andetherified with triphenylmethyl chloride following the procedure ofPreparation 3 to yield the 3-ethyl enol ether of 2l-triphenylmethoxyq4,17(20)-[cis]-pregnadiene-3,11-dione. This latter compound was thenreacted in anhydrous benzene with methyl lithium following the procedureof Example v1 to yield the 3-ethyl enol ether ofllot-methyl-llB-hydroxy-21-triphenylrnethoxy-4,l7(20)-[cis]-pregnadiene-3-one, a white crystallinesolid.

By substituting the 3-methyl, the 3-benzyl and the 3- octyl enol ethersof 2l-hydroxy-4,l7(20)-[cis]-pregnadiene-3,l1dione, made by the processof Preparation'4, followed ,by hydrolysis as above, other ZI-hydrocarbohetherscan be prepared by the process of Preparation 3, he, bysubstituting-such hydrocarbon halides as methyl chloride, butyl bromide,or benzyl chloride for the triphenylmethyl chloride. Theselattercompounds can-then be reacted with lower-a-lkyl lithiums such asmethyl, ethyl, propyl, heptyl, or octyl lithium, to provide thecorresponding lle-alkylated compounds inaccordance with the procedure ofthis example.

EXAMPLE 2 11a methyl 1113,21 dz'hydroxy 4,17(20) [cis] pregnadiene-3-one(VI) A suspension of 200 milligrams (0.32 millimole) of the 3-ethyleneglycol ketal of lla-methyl-llfi-hydroxy- 21,: triphenylmethoxy 4,17(20)pregnadiene 3-one in twenty milliliters of methanol containing onemilliliter of 1 N hydrochloric acid was stirred at room temperature fortwo days, during which time the suspended solid gradually dissolved. Thesolution was mixed with fifteen milliliters of 1.3 percent aqueoussodium bicarbonate and then, evaporated to dryness. The residue wastriturated with thirty milliliters of benzene. The benzene solution waspoured over a thirty gram column of Florisil (synthetic magnesiumsilicate). The column was developed with sixty milliliter portions ofsolvent of the following composition and order: six of Skellysolve B(hexane, hydrocarbons), six of Skellysolve B plus five percent acetone,six of Skellysolve B plus ten percent acetone, six of Skellysolve B plus25 percent. acetone andsix, of acetone. The middle four Skellysolve Bplus 25v percent acetone eluate fractions contained 78 milligrams of11a-methyl-11fl-21-dihydroxy-4,l7(20)-[cis]- pregnadiene-S-one which,when recrystallized from ethyl acetate, melted at 188 to 192 degreescentigrade and had the analysis below.

Calculated for C l-1 0 C, 76.70; H, 9.36. Found: C, 76.31; H, 9.50.

EXAMPLE 3 11/3 hydroxy 11a methyl 21 acetoxy 4,17(20) [cis]-pregnadiene-3-one (VII) A solution of about 2000 milligrams of1113,21-dihydroxy 11a methyl-4,17(20)-[cis]-pregnadiene-3-one in 25milliliters of pyridine was mixed with 25 milliliters of aceticanhydride and the whole was then maintained atroom temperature for threedays whereafter the mixture was poured over crushed ice. Theprecipitated oily 113- hydroxy 11oz methyl 21 acetoxy 4,17(20) lcis]-pregnadiene-3-one was recovered by extraction with methylene chlorideand then chromatographed over a column of fifty grams of Florisil(synthetic magnesium silicate).- Thecolumn was developed with350-milliliter portions of Skellysolve B (hexane hydrocarbons)containing increasing percentages of acetone. The eluate fractionscontaining seven percent acetone eluted 1.994 grams of1lfl-hydroxy-l1a-methyl-21-acetoxy-4,17(20)- [cisl-pregnadiene-3-onewhich, when crystallized from a mixture of ethyl acetate and SkellysolveB, melted at l07l 13 degrees centigrade.

Similarly, other 21-organic carboxylic acid esters of 116,21 dihydroxy11a methyl 4,17(20) [cis] pregnadiene-3-one are prepared wherein theZl-acyloxy group is formyloxy, propionyloxy, butyryloxy, valeryl- OXY,hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, phenylacetoxy, orthe like, by contacting11,8,21-dihydroxy'lla-methyl-4,17(20)-pregnadiene-3-one with anappropriate acylating agent, e.g., the anhydride or acid halide of theselected acid in a solvent such as, for ex: ample, benzene, toluene,acetic acid, or the like.

EXAMPLE 4 J: methyl 115,170 dihydroxy 21 acetoxy 4 pregnene-3,20-di0ne(VIII) To a solution of 681 milligrams of lla-methyl-llflhydroxy- 21acetoxy 4,17(20) [cis] pregnadiene- 3-one-dissolved in 33.5 millilitersof tertiary butyl alcohol was added 0.4 milliliter of pyridine followedby a solution' of 730 milligrams of N-methylmorpholine oxide peroxidein- 3.47 milliliters of tertiary butyl alcohol and 0.56 milligramofosmium tetroxide in 1.02 milliliters of tertiary butyl alcohol. TheN-methylmorpholine oxide peroxide was prepared by the reaction ofN-methylmorpholine with two molar equivalents of hydrogen peroxideintertiary butyl alcohol. The mixture was maintained at about 25 degreescentigrade for twentyfive hours and then mixed with 370 milligrams ofMagnesol filter aid and 9.2 milliliters of aqueous 0.5 percent sodiumhydrosulfite solution. After one-half hour the mixture was filtered andmost of the tertiary butyl alcohol distilled from the filtrate atreduced pressure and at a temperature less than'sixty degreescentigrade. The concentrate was diluted with about 35 milliliters ofwater and, extracted with. four 25-mililliter portions of methylenechloride. The combined extracts were washed with sixty milliliters ofwater, filtered through anhydrous sodium, sulfate and concentrated todryness at reducedv pressure. The resultant oil was redissolved inmethylene'chloride and chromatographed over a column offifty grams ofacid-washed alumina, the height: diameter ratio of the column beingabout 4:1. Elution was carried out by a solvent gradient technique. Theinitial eluting solvent was methylene chloride. The initial volume ofsolvent in the reservoir above the column was 1,000 milliliters. Thisvolume was maintained constant by the gradual addition of 800milliliters of methylene chloride plus twenty percent acetone. When thissolvent had all been added to the reservoir, 800 milliliters ofmethylene chloride plus sixty percent acetone was added to the reservoirin the same manner. When this solvent had all been added to thereservoir, the solvent gradient elution of the column was stopped, thesolvent remaining in the reservoir discarded and the column was strippedwith methanol. The desired product was obtained by evaporation of the1,150 milliliters of eluates which immediately preceded the methanoleluates. The 268 milligrams of crude product thus-obtained wascrystallized from ethyl acetate to give lla-methyl-llBJh-dihydroxy 21acetoxy-4-pregnene-3,20-dione melting at 192 to 197 degrees-centigrade.

EXAMPLE 5 11a methyl ]lfi,l7a,2l trihydroxy 4 pregnene 3,20-dione (VIII)A solution of 418 milligrams of lla-methyl-hydrocortisone acetate infour milliliters of methanol was freed of oxygen gas by bubblingnitrogen therethrough. A solution of 404 milligrams of potassiumbicarbonate in four milliliters of water was similarly freed of oxygen.The two solutions were mixed at a temperature of between eighteenandtwenty degrees centigrade and in a nitrogen atmosphere. The temperatureof the solution rose to between 24 and 26 degrees Centigrade. Themixture was stirred at room temperature for five hours while protectingit from atmospheric oxygen with nitrogen. At the end of five hours thesolution was neutralized with very dilute acetic acid. The neutralizedsolution was concentrated by distillation at room temperature and thenchilled in a refrigerator for about sixteen hours. The thus-precipitated1la-methyl-hydrocortisone was filtered, washed with ice water and thendried.

llot-methyl-hydrocortisone can also be prepared by substituting lla-methyl-l l;8,2l-dihydroxy-4,l7 (20)-[cis]- pregnadiene-3-one as thestarting steroid in Example 4.

It is to be understood that the invention is not to be limited to theexact details of operation described, as obvious modifications andequivalents will be apparent to one skilled in the art, and theinvention is therefore to be limited only by the scope of the appendedclaims.

We claim:

1. 3-hydrocarbon enol-Zl-hydrocarbon diethers of 11ozlower-alkyl 115,21dihydroxy 4,17(20) pregnadiene-3-one represented by the followingformula:

lower-alkyL (FHr-O-hydrocarbon References Cited in the file of thispatent UNITED STATES PATENTS 2,668,816 Miescher Feb. 9, 1954 2,683,724Hogg et a1. July 13, 1954 2,774,776 Hogg et a1. Dec. 18, 1956

1. 3-HYDROCARBON ENOL-21-HYDROCARBON DIETHERS OF 11ALOWER-ALKYL -11B,21 - DIHYDROXY - 4,17(20) - PREGNADIENE-3-ONE REPRESENTED BY THEFOLLOWING FORMULA: